Adjuvant treatment with the tyrosine kinase inhibitor osimertinib will likely become a new standard of care in patients with EGFR-mutant non–small cell lung cancer. In the phase III ADAURA trial, 90% of patients with stage II–IIIA disease who received osimertinib were alive and free of cancer at 2 years, compared with 44% who received a placebo—results considered so striking that researchers unblinded the trial early.

Adjuvant treatment with the EGFR tyrosine kinase inhibitor (TKI) osimertinib (Tagrisso; AstraZeneca) in patients with EGFR-mutant non–small cell lung cancers (NSCLC) significantly improved disease-free survival (DFS) in the phase III ADAURA trial. Indeed, based on an interim analysis of osimertinib's efficacy, an independent data-monitoring committee recommended in April that the trial be unblinded—2 years ahead of schedule. The study is bound to change clinical practice, researchers said.


Molecular structure of osimertinib.

ADAURA data were presented at the 2020 American Society of Clinical Oncology Annual Meeting on May 31 by Roy Herbst, MD, PhD, of Yale Cancer Center in New Haven, CT (J Clin Oncol 38: 2020 (suppl; abstr LBA5).

Adjuvant cisplatin-based chemotherapy is the standard of care for patients with stage II–IIIA NSCLC, as well as for high-risk patients with stage IB disease. However, recurrence rates are troublingly high, said Herbst, which prompted researchers to test osimertinib—a first-line therapy for patients with advanced, EGFR-mutant NSCLC—after surgery.

Researchers enrolled 682 patients in the trial, all of whom had stage IB, II, or IIIA NSCLC harboring EGFR exon 19 deletions or exon 21 L858R mutations. Half were assigned to take 80 mg of osimertinib daily for up to 3 years; the other half received a placebo. Ninety percent of patients with stage II–IIIA disease who received osimertinib were alive and free of cancer at 2 years, compared with 44% who received a placebo—and patients treated with osimertinib had an 83% reduction in the risk of disease recurrence or death.

When patients with stage IB disease were included in the analysis, DFS at 2 years was 89% among patients who received osimertinib compared with 53% among those receiving placebo. Overall, treatment with osimertinib reduced the risk of disease recurrence or death by 79%. Herbst noted that osimertinib outperformed placebo regardless of factors such as sex, race, disease stage, smoking history, and use of adjuvant chemotherapy prior to ADAURA, making the study “a home run.”

Herbst characterized osimertinib as “very well tolerated”; low-grade diarrhea, dry skin, and rash were the most frequent side effects, consistent with its known safety profile. Less than 7% of patients discontinued therapy due to toxicity.

Suresh Ramalingam, MD, of the Winship Cancer Institute in Atlanta, GA, who was not affiliated with the trial, called the results “stunning.”

“The patient population with stage IIIA has a very high risk of recurrence; most of the recurrences happen in the first 2 years after surgery. Therefore, the 2-year DFS numbers provide us with an excellent indication of the high degree of benefit with osimertinib,” he said. Further, because chemotherapy and EGFR TKIs may have additive/synergistic effects, “I feel that chemotherapy followed by osimertinib will be a standard approach.”

Discussant David Spigel, MD, of Sarah Cannon Cancer Institute in Nashville, TN, tempered expectations, noting that overall survival data are not yet mature and that variations in surgical practice or prior chemotherapy might confound the results.

Spigel also reflected on another adjuvant trial, appropriately named ADJUVANT, in which patients with EGFR-mutant NSCLC received either gefitinib (Iressa; AstraZeneca) or chemotherapy (Lan Onc 2018;19:139–48). “The advantage for patients who were on gefitinib was maintained until after they came off 2 years of gefitinib,” he said. That made him wonder: “What is osimertinib doing? Is it eliminating disease? Or is it simply controlling and deferring disease that cannot be eradicated? And what happens after 3 years of osimertinib?”

However, “the one question I continue to come back to is the one I get asked in nearly every clinic: What would I do if it were me or one of my family members?” said Spigel. Simply put, “I would choose osimertinib.” –Suzanne Rose

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